312 - A masterclass in lactate: metabolic fuel, implications for diseases, and therapeutic potential

KEYPOINTS

• 01

  Lactate is a fuel, not a waste product—a '100-year mistake'.

  Brooks, a Berkeley exercise physiologist who proposed the lactate shuttle, says lactate is not an innocent bystander but a participant in powering muscle and all cells. Otto Meyerhof's work—Nobel Prize in 1922, shared with A.V. Hill—led to teaching that lactate is a dead-end byproduct of oxygen-poor glycolysis; Brooks argues we've taught glycolysis wrong for a century.

• 02

  Glycolysis normally ends in lactate, which is then shuttled and oxidized.

  Lactate is produced continuously, even at rest, and moves between cells and tissues to be burned in mitochondria or converted to glucose in the liver (gluconeogenesis, the Cori cycle). In his tracer studies, about 75–80% of lactate disposal during exercise is oxidation.

• 03

  Most carbon for lactate comes from muscle glycogen.

  About 80% of the body's glycogen sits in skeletal muscle and roughly 20% in the liver. During exercise, glycogen-derived lactate becomes a major fuel distributed to heart, brain, liver and other muscles.

• 04

  Lactate transporters (MCTs) and mitochondrial machinery enable the shuttle.

  Monocarboxylate transporters move lactate across membranes; there are now more than four known, the first characterized around 2000. Brooks published finding MCTs on mitochondrial membranes around 1995. Training roughly doubles transporter and mitochondrial capacity—the 'cartoon' muscle cell going from 50 to 100 MCTs.

• 05

  Training expands mitochondria far more than VO2 max.

  Training can increase mitochondrial mass perhaps 100% while VO2 max rises only 10–15%—a 1967 study in rats by John Holloszy showed this. Mitochondria form a branched network ('reticulum'), so mass and volume matter more than counting individual organelles.

• 06

  Lactate thresholds reflect clearance capacity, not just production.

  A brisk walk keeps lactate around 1–1.5 mmol; about 4 mmol is the classic threshold a fit person can sustain 30–40 minutes. Elite athletes produce lots of lactate at a given relative intensity but clear it rapidly. Venous lactate from a hard-working muscle might hit 10–12 mmol.

• 07

  Lactate fuels the brain, especially when it's stressed.

  George Cahill's fasting studies showed people with glucose around 55 mg/dL got about half their brain's fuel from BHB. Brooks's group studies lactate for traumatic brain injury; colleagues in Switzerland give hypertonic lactate to TBI patients who appear to do better, and people can be clamped at about 4 mmol safely, with some reaching 6–8 mmol.

• 08

  In disease, lactate signals metabolic inflexibility.

  In insulin resistance, muscle struggles to take up glucose via GLUT4, so lactate patterns change. Sepsis lactate of 10 mmol is bad news—but standard assays measure only L-lactate, and Peter wonders whether D-lactate might also matter. Metformin users face increased lactic-acidosis risk when dehydrated.

• 09

  After an oral glucose load, the liver buffers most of the sugar and lactate rises.

  With a 75 g oral glucose tolerance test, blood glucose may double from ~75 to ~150 mg/dL—only about 5 g more glucose in circulation—so ~70 g must go elsewhere. Studies with 13C-labeled glucose and grain show the liver sequesters about 80% and releases it later; lactate spikes within 5 minutes and peaks around 15.

• 10

  Lactate is also a signaling molecule.

  Brooks says lactate can activate hundreds of genes (he cites about 500), affecting mitochondrial biogenesis and other adaptations—part of why exercise is so broadly beneficial.

• 11

  The Warburg effect: cancer cells make lactate even with plenty of oxygen.

  Otto Warburg, Meyerhof's professor in Germany, observed that cancer cells break down glucose to lactate under fully aerobic conditions—room air, with more oxygen than tissues ever see. Brooks reframes this as cancers exploiting lactate's roles as fuel and signal, rather than simply 'avoiding' mitochondria, a point Peter challenges him to explain.

• 12

  Fiber recruitment and clearance explain everyday fatigue.

  Light work like writing uses type I fibers, which oxidize lactate well. Lifting heavier loads or working overhead recruits type II fibers that produce more lactate and clear it less well, which is why something as simple as changing a light bulb overhead can feel surprisingly fatiguing. Ketones such as BHB enter cells through the same MCT transporters as lactate, so fuels compete—more glucose means less fat, and vice versa.